The field of viral chemotherapeutics has recently developed in response to the particularly challenging problems presented with respect to the diagnosis and treatment of viral diseases. Of particular interest is the development of compounds effective against retroviruses, most particularly the HIV virus.
The effectiveness of any antiviral chemotherapeutic naturally depends on many factors including the identification of the specific virus, an understanding of its infectivity, life cycle, replication, and spread within the infected host.
All viruses must replicate and transcribe their nucleic acids into messenger RNA which in turn translates into proteins for progeny virions. For DNA viruses, the virus synthesizes its own DNA polymerase enzyme which uses the cell's supply of purines and pyrimidines to make additional copies of the viral DNA.
Retroviruses are characterized in that they are able to synthesize DNA from the RNA template which comprises their genetic material via a polymerase enzyme "reverse transcriptase" and are therefore characterized as retroviruses. This DNA, which corresponds to the RNA version of the viral genome, is then incorporated into the host cell genome and viral DNA is synthesized in the course of the normal host cell processes. The HIV virus is characteristically a retrovirus and possesses the enzyme reverse transcriptase.
Antiviral compounds with various modes of action are known in the art. For example, a class of compounds known as nucleoside analogs exhibit broad antiviral activity by interfering with the viral life cycle.
These "fraudulent" nucleosides (or 2',3' dideoxy derivatives) are analogs of the normal DNA or RNA building blocks; adenosine, thymidine, cytidine, guanosine or uridine. However, unlike their normal counterparts these compounds cannot be used in normal DNA or RNA synthesis. In the cell these fraudulent nucleosides deceive the virus into thinking they are normal DNA or RNA building blocks. The "fraudulent" counterpart is utilized in the viral life cycle ultimately resulting in viral suicide.
Unfortunately, most of these antiviral substances which are nucleoside analogs are not specific inhibitors of only viral processes. Most of these compounds will interfere to a greater or lesser degree with normal molecular processes of the host cell resulting in toxic effects on uninfected cells.
This is particularly true with the 2',3' dideoxynucleoside analogs such as 2',3' dideoxycytidine (ddC) and the analogs thereof. ddC in particular causes peripheral neuropathy which results in tingling, numbing and pain which may require potent pain killers such as morphine when administered at the dosages which are effectively antiviral.
In the case of a 2',3' dideoxyadenosine particularly high dosages are necessary to be effectively antiviral.